Most patients prefer to take orally administered medicaments over other routes of administration. However, in order to be acceptable to patients, an oral drug product must be easily swallowed and without unpleasant or bitter taste or other undesirable organoleptic properties.
Many drug substances, also commonly referred to as active pharmaceutical ingredients (API), exhibit a rather poor taste. A poor taste often means a significant level of bitterness, but may also involve other unpleasant sensations such as a burning, stinging, metallic, or astringent mouthfeel.
While taste masking is generally rather easy to achieve with a conventional tablet which may be coated with a suitable polymeric coating, and also in the case of a capsule formulation wherein the capsule shell itself provides a barrier which prevents contact between the active ingredient and the oral mucosa of the patient during administration, it is much more challenging to mask the taste of a compound having a poor taste when formulated as a dispersible, effervescent, or orally disintegrating dosage form or as granules for direct oral administration (“direct-to-mouth granules”), because in these cases the dosage unit is not swallowed as a whole, but the formulation comes into substantial contact with the oral mucosa. In the case of effervescent formulations, the drug typically dissolves in a larger amount of water, such as 200 mL, and in this diluted form, sufficient taste masking may be achieved through the incorporation of sweetening agents and flavours. Most challenging in terms of taste is the formulation of the active ingredient in dosage forms whose administration potentially allows the drug to contact the oral mucosa in concentrated form, as in the case of orally disintegrating tablets or granules for direct oral administration. On the other hand, such dosage form designs are highly desirable for high-dose drugs because of their excellent swallowability even without water.
Further technical challenges arise when the API is not easily processable, for example due to sensitivity to thermal stress or moisture. Another particular difficulty is the processing of mechanically unstable API particles, especially of drug particles which represent agglomerates or granules. Poor mechanical stability of the API particles means that they cannot easily be coated as the heat and mechanical stress involved in most coating processes would lead to the diminution or disintegration of the agglomerate, which would cause the generation of undesirable API dust and a substantially reduced coating efficiency. In result, the taste-masking effect would not be sufficient, at least not if the API is to be incorporated within an oral (direct-to-mouth) granule formulation or an orally disintegrating tablet.
Nevertheless, effective taste-masking may require that a coating is provided on the surface of the active ingredient. The coating serves as a physical barrier layer between the active ingredient and the patient's taste buds and olfactory receptors. In addition, a coating may be useful also to protect a sensitive or labile active ingredient during storage.
In principle, taste-masking coatings may be polymeric film coatings or lipidic coatings. Polymeric coating systems are sprayed onto drug cores as aqueous or organic solutions or dispersions. A disadvantage of organic solvents is their need for special equipment and their negative impact on the environment. Aqueous coating systems also consume substantial energy, as the polymeric coating material must be heated above its film-forming temperature in order to coalesce, and the removal of water require more extensive drying than that of typical organic solvents. Moreover, many polymeric coating systems show curing effects, i.e. their properties change over time, so that the drug dissolution behaviour may become compromised during storage.
In principle, a lipid coating may be applied to API particles by various thermal processing methods such as melt extrusion, spray congealing, melt coating in a mixer, fluid-bed coating, and the like.
Lipidic coating systems, such as coatings based on waxes like carnauba wax, do not require a solvent to be applied to drug-containing cores: They may often be used as melts in hot-melt coating processes. On the other hand, these types of coatings, due to the poor water solubility of its main constituents, also tend to have substantial negative impact on the drug's release profile, especially if rapid drug release is required. For example, Sinchaipanid et al (Powder Technology, 2004, 141, 203-209) describe the hot-melt coating of granulated propranolol hydrochloride pellets using a coating consisting of a mixture of Precirol® ATO5, (glyceryl palmitostearate, which comprises primarily diglycerides of palmitic and stearic acid) and Gelucire® 50/02 (saturated polyglycolysed glycerides). Compared to uncoated propranolol pellets, addition of the coating resulted in a significant decrease in drug release rate—in fact providing for regulated and controlled release of the drug. In cases where immediate release of a drug is required wax coatings are thus often not successful.
The stability of a lipidic or waxy taste-masking coating itself over time can also impact the release profile of the active ingredient. The conversion of an initially formed polymorph of a coating excipient to a thermodynamically more stable crystal form over time during the course of storage, sometimes also triggered by an exposure to different environmental conditions, can lead to significant and undesirable variations in the drug dissolution profile of the composition.
Furthermore, the hot-melt processing conditions may be critical to temperature-sensitive drug compounds. Depending on the type of lipidic or waxy coating material, the coating process are sometimes conducted at temperatures of higher than 60° C., and sometimes also higher than 80° C. or even 100° C. Depending on the type of equipment that is used, additional disadvantages such as high shear or pressure may make the coating process unattractive for certain APIs, in particular mechanically unstable API particles such as agglomerates.
WO 2010/037543 A1 describes the extrusion of lipid pellets for taste masking. The method requires the mixing of the active ingredient with a lipid mixture comprising a hard fat and glycerol trimyristate or glycerol distearate, followed by cold extruding the mixture and spheronising the extrudate to obtain pellets or spherical granules. Provided that a sufficient amount of lipid material is used, a coating is formed which completely covers the surface of the pellets and which preferably has a thickness of at least 5 nm. A major disadvantage is however that the release of the incorporated drug substance is substantially decelerated, even in the case of a readily water-soluble compound such as sodium benzoate. The inventor reports that even after 45 min of dissolution testing at 37° C., the drug is not completely released from the formulation.
WO 2008/071407 A2 discloses immediate or rapid release pellets comprising cefpodoxim, an antibiotic compound having a poor taste. The pellets exhibit a taste-masking coating comprising carnauba wax and a hydrogel former such as a cellulose polymer derivative, alginate or gum. It is mentioned in the document that many lipophilic substances, such as cocoa butter or Precirol®, are prone to polymorphic changes during storage. As the structural changes would lead to inconsistencies in the dissolution profiles, such compounds are deemed to be unsuitable for use as coating excipients for these pellets. The document therefore teaches the use of waxes such as carnauba wax which have a high melting range and which do not exhibit any polymorphic changes.
U.S. Pat. No. 5,891,476 discloses acetaminophen particles or granules coated with a non-polymorphic waxy component such as carnauba wax and optionally other lipid components and/or surfactants. According to the document, the use of such waxes removes the risk of variable dissolution rates resulting from changing morphology of the coating over time and under different conditions.
However, a disadvantage in using waxy components having a high melting point such as carnauba wax (melting range approx. 82 to 86° C.) in hot-melt coatings is that the active ingredient itself may also be subjected to the higher temperatures required to maintain the coating components in melt-phase during the coating process. Higher temperatures during processing can increase the degradation of thermo-labile active ingredients. Moreover, hot-melt coating processes involving molten carnauba wax are very difficult to handle because the coating composition must be kept at even higher temperatures, e.g. at about 100° C. or higher, and since this wax solidifies very rapidly upon cooling down, it tends to clog the tubes through which it is pumped to the spray nozzle, as well as the nozzle itself.
WO 2010/070028 A1 discloses various taste-masked, hot-melt coated compositions incorporating the active ingredients acetaminophen, ranitidine, and caffeine. The coatings comprise, as a meltable lipophilic excipient, stearic acid, Precirol ATO 5 (a mixture of mono-, di- and triglycerides of palmitic and stearic acid), or Compritol 888 ATO (glyceryl behenate). The coatings further comprise a release compound, i.e. a compound which enhances the disintegration of the taste-masking layer in the gastrointestinal fluid, such as by the formation of pores or holes through swelling (e.g. Amberlite IRP 88) or carbon dioxide release (e.g. calcium carbonate); and a surfactant or other substance (e.g. PEG 3000 or Tween 20) which is incorporated to achieve a homogeneous distribution of the release compound in the meltable lipophilic excipient. However, the resulting coating compositions are rather complex. Due to the insolubility of the release compound in the meltable lipophilic compound, there is a risk of phase separation during the coating process, leading to poor reproducibility. Moreover, as the document is silent on this aspect, it is unclear whether the release profiles achieved with such complex and inherently incompatible coating compositions are stable under storage conditions.
US 2010/0092569 A1 relates to the taste-masking of conjugated linoleic acid compounds by suspending an adsorbate of the active ingredient on silica powder in a molten lipid matrix and subsequent spray cooling, such as to form coated particles. The lipid matrix comprises triglycerides of C16, C18, C20 and C22 saturated fatty acids and 3 wt.-% of an unidentified emulsifier whose function is to ensure a homogeneous dispersion of the active ingredient in the molten lipid. The purpose of the coating is to protect the light- and air-sensitive linoleic acid compound from degradation. The taste-masked product is used as an additive in animal feed.
However, the preparation of a melt suspension involves the full exposure of the active ingredient to temperatures higher than the melting range of the lipid, in the present case about 70° C., which may be acceptable in the case of some active ingredients or in the case of animal feeds, but not for temperature-sensitive pharmaceutical compounds for human use. Moreover, the document is silent as to the resulting dissolution profiles, which do not appear to have any relevance in this case.
It is an object of the invention to provide an improved method for the taste-masking of drug substances that are mechanically unstable, such as agglomerated API particles. Moreover, it is an object to provide an improved taste-masked form of agglomerated drug particles which are immediate release, i.e. which exhibits rapid drug dissolution and a stable dissolution profile. It is also an object to provide improved methods and compositions for the masking of the taste of agglomerated drug particles which are heat or moisture sensitive. A further object is to provide improved pharmaceutical compositions comprising taste-masked agglomerated drug particles with rapid drug dissolution. A yet further object is to provide taste-masked compositions which may be manufactured at moderate, as well as processes by which taste-masked compositions of sensitive compounds may be prepared. Moreover, it is an object to overcome one or more of the limitations or disadvantages associated with the prior art. Other objects will become clear on the basis of the description and the claims.
These and other objects are achieved by the subject-matter as defined in the independent claims below, with particular embodiments outlined in the dependent claims.